Li Ning1, Renata Jaskula-Sztul, Muthusamy Kunnimalaiyaan, Herbert Chen. 1. Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI, USA.
Abstract
BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that frequently metastasizes and has few treatments. This study was aimed at assessing the antitumor effects of suberoyl bishydroxamic acid (SBHA) in an in vivo model of MTC. METHODS: Nude mice were injected with human MTC cells, and the groups were treated with SBHA (200 mg/kg) or vehicle (dimethyl sulfoxide) in saline injection every other day for 12 days. Tumors were measured every 4 days and collected at 12 days for Western blot analysis. RESULTS: Treatment with SBHA resulted in an average 55% inhibition of tumor growth in the treatment group (P < .05). Analysis of SBHA-treated MTC tumors revealed a marked increase in the active form of Notch1 (NICD) with a concomitant decrease in achaete-scute complex-like 1 (ASCL1), a downstream target of Notch1 signaling, as well as the neuroendocrine tumor marker chromogranin A. Importantly, SBHA treatment resulted in an increase in protein levels of p21(CIP1/WAF1), p27(KIP1), cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase and concomitant with a decrease in cyclin D1 and cyclin B1, indicating that the growth inhibition was due to both cell cycle arrest and apoptosis. Moreover, SBHA downregulated cell survival proteins Bcl-2 and Bcl-X(L), but upregulated apoptotic proteins Bax, Bad, and Bmf. CONCLUSION: These results demonstrate that SBHA inhibits MTC growth in vivo. SBHA is a promising candidate for further preclinical and clinical studies in MTC.
BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that frequently metastasizes and has few treatments. This study was aimed at assessing the antitumor effects of suberoyl bishydroxamic acid (SBHA) in an in vivo model of MTC. METHODS:Nude mice were injected with human MTC cells, and the groups were treated with SBHA (200 mg/kg) or vehicle (dimethyl sulfoxide) in saline injection every other day for 12 days. Tumors were measured every 4 days and collected at 12 days for Western blot analysis. RESULTS: Treatment with SBHA resulted in an average 55% inhibition of tumor growth in the treatment group (P < .05). Analysis of SBHA-treated MTC tumors revealed a marked increase in the active form of Notch1 (NICD) with a concomitant decrease in achaete-scute complex-like 1 (ASCL1), a downstream target of Notch1 signaling, as well as the neuroendocrine tumor marker chromogranin A. Importantly, SBHA treatment resulted in an increase in protein levels of p21(CIP1/WAF1), p27(KIP1), cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase and concomitant with a decrease in cyclin D1 and cyclin B1, indicating that the growth inhibition was due to both cell cycle arrest and apoptosis. Moreover, SBHA downregulated cell survival proteins Bcl-2 and Bcl-X(L), but upregulated apoptotic proteins Bax, Bad, and Bmf. CONCLUSION: These results demonstrate that SBHA inhibits MTC growth in vivo. SBHA is a promising candidate for further preclinical and clinical studies in MTC.
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